Trial Title:
ETC-159 In Combination With Pembrolizumab In Advanced MSS/pMMR Ovarian Cancers
NCT ID:
NCT06513624
Condition:
With MSS/pMMR Advanced, Platinum-resistant Ovarian Cancer
Conditions: Official terms:
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Zoledronic Acid
Denosumab
Pembrolizumab
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Patients will undergo screening procedures to determine eligibility within 28 days prior
to the initial administration of ETC-159 in combination with pembrolizumab. ETC-159 in
combination with pembrolizumab will be administered in 21-day cycles (1 cycle: 21 days).
ETC-159 will be dosed every other day. Pembrolizumab will be dosed IV Q3W. Tumor response
assessments will be done every 6 weeks (2 cycles) prior to starting the cycle starting at
C3D1 (- 7 days) until C9D1 (- 7 days); thereafter every 12 weeks (4 cycles) starting at
C13D1 (- 7 days) and at EOT, until disease progression or start of another anti-cancer
therapy according to RECIST v1.1.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
ETC-159
Description:
ETC-159 will be administered orally.
Arm group label:
ETC-159
Intervention type:
Drug
Intervention name:
Pembrolizumab
Description:
Pembrolizumab will be administered intravenously.
Arm group label:
ETC-159
Intervention type:
Drug
Intervention name:
Denosumab / Zoledronic Acid
Description:
Denosumab will be administrated subcutaneously. Zoledronic Acid will be administered
intravenously if denosumab has no response.
Arm group label:
ETC-159
Summary:
This is an open-label, single-arm, investigator-initiated study conceived as a dose
expansion cohort of the study D3-002, which evaluated ETC-159 in combination with
pembrolizumab in solid tumors.
Detailed description:
Hypothesis:
Wnt pathway inhibition with ETC-159 in combination PD1 checkpoint inhibition is safe and
effective for the treatment of patients with advanced MSS/pMMR ovarian cancer.It is
hypothesized that, ETC-159, as a selective PORCNi, will lead to increased immune
infiltration and therefore may turn "cold" tumors into "hot" tumors that may then be
responsive to checkpoint inhibitor
Primary Objectives:
1. To evaluate the preliminary clinical activity of ETC-159 in combination with
pembrolizumab according to RECIST v1.1, in patients with advanced or metastatic,
platinum-resistant MSS/pMMR ovarian cancer
2. To assess the safety of ETC-159 at the dose of 8 mg every other day (the recommended
dose [RD] identified in safety segment) in combination with pembrolizumab.
Secondary Objectives:
1. To further assess the efficacy of ETC-159 in combination with pembrolizumab
2. To evaluate the PK of ETC-159 in combination with pembrolizumab in patients.
Exploratory Objectives:
1. To evaluate the effect of ETC-159 administered orally every other day in combination
with pembrolizumab with bone protective treatment (denosumab and subsequently
zoledronic acid if no response is observed with denosumab) on bone turnover markers
as potential downstream markers of Wnt signaling (β-CTX).
2. To correlate available tumor genomic profile with clinical data.
3. To evaluate the effect of ETC-159 treatment on :
- Pharmacodynamic biomarker (Axin2 mRNA expression levels) in hair follicles.
- Gene expression levels and PD-L1 protein expression measured in FFPE-tumor
tissue (if sufficient tissue is available).
4. To determine change in serum levels of cancer antigen 125 (CA-125).
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Is capable of understanding the written informed consent, provides signed and
witnessed written informed consent, and agrees to comply with the protocol
requirements.
2. Is female, and age 21 years or older (Singapore sites) at pre-screening or
screening.
3. Has histologically or cytologically confirmed, advanced or metastatic ovarian cancer
with a platinum free interval of less than 6 months from prior platinum based
treatment or for whom platinum therapy is no longer an option according to the
treating physician
4. Has MSS/pMMR tumors as determined by immunohistochemistry (IHC), polymerase chain
reaction (PCR), or next-generation sequencing (NGS).
5. Has objective (assessable through clinical signs, symptoms, and/or laboratory
findings) and radiologically-confirmed progression of disease at Screening.
6. Has measurable disease as determined by RECIST v1.1 (Appendix 4, Section 12.4).
Target lesions should not be selected in previously irradiated fields unless there
is clear evidence of progression.
7. Has ECOG performance of status 0 to 2 at Screening.
8. Has life expectancy of at least 3 months at Screening.
9. Has adequate organ function at Screening, including the following (noting that
repeated tests Screening should not be performed unless there are sufficient reasons
to assume the patient would meet the inclusion criteria with re-testing).
- Absolute neutrophil count ≥1.0 × 109/L
- Platelet count ≥100 × 109/L (without transfusions within 21 days prior to Day 1
of Cycle 1
- Hemoglobin ≥9 g/dL
- Prothrombin time and partial thromboplastin time within ≤1.5 × upper limit of
normal (ULN)
- International normalized ratio (INR) ≤1.5 × ULN Note: If the patient is on
allowed anti-coagulants the INR and coagulation parameters should be in the
therapeutic range
- Total bilirubin ≤1.5 × ULN
- Transaminases (AST and/or alanine aminotransferase ≤2.5 × ULN (<5 × ULN if
liver metastases)
- Calculated creatinine clearance ≥40 mL/min (Cockroft and Gault formula)
- Total calcium (corrected for serum albumin) within normal limits prior to Day 1
of Cycle 1 (supplementation is permitted).
Note: Patients with grade 1 changes can be included as long as they are asymptomatic
and can receive supplementation during the study.
o Magnesium ≥the lower limit of normal (LLN) prior to Day 1 of Cycle 1
(supplementation is permitted).
Note: Patients with grade 1 changes can be included as long as they are asymptomatic
and can receive supplementation during the study.
10. Patients must have a T-score greater than -1 to be eligible, however, patients with
osteopenia (defined as a T-score of -1 to -2.5 at the left or right total hip, left
or right femoral neck, or lumbar spine [L1 to L4] as determined by DEXA at
Screening) are eligible to participate and will receive calcium and vitamin D
supplements during the study. Patients with osteoporosis (T-score of <-2.5) must be
excluded.
Note: T-score should be calculated according to local requirements by DEXA scan for
the purpose of determining eligibility.
11. Is capable of swallowing study medication and following directions regarding taking
study drug or has a daily caregiver who will be responsible for administering study
drug.
12. Has a negative serum pregnancy test at Screening or a negative urine pregnancy test
within 7 days prior to Day 1 Cycle 1 prior of treatment (applies to females of
childbearing potential only).
13. For all patients: pre-dose and post-dose tumor biopsies are mandatory unless tumor
is inaccessible or deemed unsafe for procedure by the principal investigator.
Note: NGS reports can be collected where biopsies are not done.
Exclusion Criteria:
Subjects should not enter the study if any of the following exclusion criteria are
fulfilled:
Patients meeting any of the following criteria will be excluded from the study (note that
exclusion criteria must be assessed at the Screening Visit, unless otherwise specified):
1. Has received anti-cancer therapy including immunotherapy within 4 weeks (28 days)
prior to starting study drug or the side effects of such therapy have not resolved
to Grade ≤1 within 4 weeks prior to starting study drug or is receiving any
concomitant anti-cancer therapy.
2. Has used other investigational drugs within 4 weeks (28 days) or five half-lives
(whichever is longer) prior to the first dose of study drug.
3. Has evidence of another malignancy not in remission or history of such a malignancy
within the last 3 years (except for treated basal or squamous cell carcinoma of the
skin, or in situ cancer of the cervix).
4. Has central nervous system metastases, unless previously treated with surgery,
whole-brain radiation or stereotactic radiosurgery, and stable disease for at least
8 weeks without steroid use for at least 4 weeks (28 days) prior to the first dose
of ETC-159.
5. Has received prior radiation therapy within 4 weeks (28 days), or limited field
radiation within 2 weeks, prior to starting study drug, or the side effects of such
therapy have not resolved to Grade ≤1.
6. Has any history of direct radiation to spine or pelvis bone or definitive
chemoradiation to pelvic organs in the last 6 months prior to starting study drug,
or the side effects of such therapy have not resolved to Grade ≤1.
7. Has a history of interstitial lung disease, sarcoidosis, silicosis, idiopathic
pulmonary fibrosis, or pulmonary hypersensitivity, or pneumonitis.
8. Has received bisphosphonate therapy for osteoporosis or symptomatic hypercalcemia or
denosumab for osteoporosis within 6 months prior to starting study drug.
9. Has osteoporosis based on a T-score of < -2.5 at the left or right total hip, left
or right femoral neck, or lumbar spine (L1 to L4) as determined by DEXA scan at
Screening (for details of calculating T-score for eligibility see Inclusion
Criterion 10).
10. Has a history of symptomatic vertebral fragility fractures or any fragility fracture
of the hip, pelvis, wrist, or other location (a fragility fracture is defined as any
fracture without a history of trauma or as a result of a fall from standing height
or less).
11. Has moderate (25% to 40% decrease in the height of any vertebra) or severe (>40%
decrease in the height of any vertebra) morphometric vertebral fractures at
Screening.
12. Has a β-CTX serum level >1000 pg/mL in the morning after at least 10 hours of
fasting at Screening.
Note: Patients should begin their treatment with the bone protective treatment
(denosumab with a starting dose of 120 mg, administered SC), and continued so as to
have a β-CTX serum level ≤1000 pg/mL
13. Has thyrotropin level less than LLN at Screening
14. Has 25-hydroxy vitamin D levels less than 25 nmol/L (10 ng/mL) at screening. Note:
For patients known to have less than 25 nmol/L (10 ng/mL) 25-hydroxy vitamin D value
that would otherwise be eligible to participate in the study, a single
administration of oral vitamin D3 (cholecalciferol) of 100,000 IU or 2 × 50,000 IU
is recommended. After a single large dose of vitamin D3, the 25-hydroxy vitamin D
level is expected to return to the required range within 7 to 28 days. After the
documentation of 25-hydroxy vitamin D level normalization, maintenance treatment can
be started by means of oral administration of 1000 IU/day of vitamin D3 or higher,
based on the investigator's clinical judgement. While vitamin D3 (cholecalciferol)
is recommended for 25-hydroxy vitamin D level restoration and maintenance,
equivalent doses of vitamin D2 (ergocalciferol) can be used if vitamin D3 is not
available.
15. Has bone metastases at Screening.
16. Has a metabolic bone disease, such as hyperparathyroidism, Paget's disease, or
osteomalacia.
17. Cannot start treatment with the bone protective treatment with denosumab and/or
zoledronic acid. Cannot start treatment with the bone protective treatment with
denosumab SC, in patients requiring this treatment at the start of study.
18. Is receiving active treatment with an oral or IV glucocorticoid for ≥4 weeks (≥28
days) at a daily dose equivalent to ≥10 mg of oral prednisone within the 12 weeks
prior to starting the ETC-159.
19. Has an active autoimmune disease that has required systemic treatment in the past 2
years (i.e., with use of disease modifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy [less than 10 mg prednisone or
equivalent daily] for adrenal or pituitary insufficiency) is not considered a form
of systemic treatment.
20. Is a female patient of childbearing potential, defined as a female physiologically
capable of becoming pregnant (including a female whose career, lifestyle, or sexual
orientation precludes intercourse with a male partner, and females whose partners
have been sterilized by vasectomy or other means), unless they are using a highly
effective method for birth control throughout the study and for 12 weeks after the
EOT. Highly effective methods for birth control include the following:
- Total abstinence: This is an acceptable method when this is consistent with the
preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are
not acceptable methods of contraception.
- Female sterilization: The patient has had a surgical bilateral oophorectomy
(with or without hysterectomy) or tubal ligation at least 6 weeks prior to
taking study drug. In case of an oophorectomy alone, the reproductive status of
the patient must have been confirmed by follow-up hormone level assessment.
- Male partner sterilization: The patient has the appropriate post-vasectomy
documentation of the absence of sperm in the ejaculate. (For female patients on
the study, the vasectomized male partner should be the sole partner for that
patient.) These patients must also agree to the following:
- Use of a combination of the following (1+2):
- Placement of an intrauterine device or intrauterine system
- Barrier methods of contraception: condom or occlusive cap (diaphragm
or cervical/vault caps) with spermicidal foam, gel, film, or cream,
or vaginal suppository
- Reliable contraception maintained throughout the study and for 12 weeks
after study drug discontinuation
- Females considered post-menopausal and not of childbearing potential: The
definition applies to females who have had 12 months of natural (spontaneous)
amenorrhea with an appropriate clinical profile (e.g., age appropriate, history
of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or
without hysterectomy) at least 6 weeks prior to starting treatment. In the case
of oophorectomy alone, only when the reproductive status of the patient has
been confirmed by follow-up hormone level assessment is she considered not of
childbearing potential.
21. Is a pregnant or nursing (lactating) female, where pregnancy is defined as the state
of a female after conception and until the termination of gestation, confirmed by a
positive human chorionic gonadotropin laboratory test (>5 mIU/mL).
22. Has had a major surgical procedure within 4 weeks (28 days) from starting the study
drug. Patient has not fully recovered from all surgery-related complications to
Grade ≤1.
23. Has a history of long QT syndrome or prolonged QT interval corrected (QTc) (>460 ms)
at Screening. Both Bazett's and Fridericia's QTc are accepted and should be used
consistently through the study (either Bazett's or Fridericia's QTc).
24. Has a known clinically significant bleeding disorder or coagulopathy.
25. Is receiving or has received within 4 weeks prior to starting study drug, heparin,
warfarin, or other similar anti-coagulants, except for patients on low molecular
weight heparin or Direct-Acting Oral Anticoagulants (DOACs: factor Xa or direct
thrombin inhibitors) for treatment or prophylaxis.
26. Has severe or unstable medical conditions such as heart failure, ischemic heart
disease, uncontrolled hypertension, uncontrolled diabetes mellitus, psychiatric
condition, an ongoing cardiac arrhythmia requiring medication (Grade ≥2, according
to National Cancer Institute [NCI] CTCAE Version 4.03), or any other significant or
unstable concurrent medical illness that in the opinion of the investigator would
preclude protocol therapy.
27. Has a known history of human immunodeficiency virus, or active infection with
hepatitis B (unless DNA count < 500) or hepatitis C virus or other active bacterial,
viral, or fungal infections.
28. Has a history of gastric bypass surgery.
29. Has a serious non-healing wound, or vasculitis.
30. Has received prior treatment with an inhibitor of the Wnt-β-catenin pathway other
than the study drug in question or received wnt-immunotherapy combinations.
31. Is unwilling to or unable to comply with the protocol.
32. Patient is unable to provide tumor tissue unless approved by the lead- sponsor
investigator
33. Has received prophylactic administration of hematopoietic colony stimulating factors
(colony stimulating factors, e.g., granulocyte colony stimulating factor,
granulocyte/macrophage colony stimulating factor, pegfilgrastim, epoetin,
darbepoetin) within 4 weeks (28 days) prior to starting study drug.
34. Has recent or current active infectious disease requiring systemic antibiotics or
antifungal or antiviral treatment within 2 weeks (14 days) prior to the start of
study drug. Patients receiving prophylactic antibiotics (e.g., for prevention of
urinary tract infection or chronic obstructive pulmonary disease) are eligible.
35. Has received a live vaccine within 28 days prior to the start of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines with
attenuated live virus for injection are allowed; however, intranasal influenza
vaccines (e.g., FluMist®) are not allowed. Anti-SARS-CoV-2 live virus vaccines
developed that utilized a replication-deficient simian adenoviral vector (ChAdOx1)
should be avoided.
Gender:
Female
Gender based:
Yes
Gender description:
Is female, and age 21 years or older (Singapore sites) at pre-screening or screening.
Minimum age:
21 Years
Maximum age:
99 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
National University Hospital
Address:
City:
Singapore
Country:
Singapore
Contact:
Last name:
David Tan, MD
Phone:
6569082222
Email:
david_sp_tan@nuhs.edu.sg
Investigator:
Last name:
David Tan, MD
Email:
Principal Investigator
Start date:
November 30, 2024
Completion date:
June 30, 2027
Lead sponsor:
Agency:
National University Hospital, Singapore
Agency class:
Other
Collaborator:
Agency:
EDDC (Experimental Drug Development Centre), A*STAR Research Entities
Agency class:
Other
Source:
National University Hospital, Singapore
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06513624
